title: Inositol 1,4,5-trisphosphate receptors are essential for the development of the second heart field.
abstract: Congenital heart defects (CHDs) occur in 0.5-1% of live births, yet the underlying genetic etiology remains mostly unknown. Recently, a new source of myocardial cells, namely the second heart field (SHF), was discovered in the splanchnic mesoderm. Abnormal development of the SHF leads to a spectrum of outflow tract defects, such as persistent truncus arteriosus and tetralogy of Fallot. Intracellular Ca(2+) signaling is known to be essential for many aspects of heart biology including heart development, but its role in the SHF is uncertain. Here, we analyzed mice deficient for genes encoding inositol 1,4,5-trisphosphate receptors (IP(3)Rs), which are intracellular Ca(2+) release channels on the endo/sarcoplasmic reticulum that mediate Ca(2+) mobilization. Mouse embryos that are double mutant for IP(3)R type 1 and type 3 (IP(3)R1(-/-)IP(3)R3(-/-)) show hypoplasia of the outflow tract and the right ventricle, reduced expression of specific molecular markers and enhanced apoptosis of mesodermal cells in the SHF. Gene expression analyses suggest that IP(3)R-mediated Ca(2+) signaling may involve, at least in part, the Mef2C-Smyd1 pathway, a transcriptional cascade essential for the SHF. These data reveal that IP(3)R type 1 and type 3 may play a redundant role in the development of the SHF.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Megumi
authors.initials: M
authors.lastname: Aramaki
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kodo
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamagishi
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamagishi
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology; D006352:Heart Ventricles / Q000002:abnormalities; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009124:Muscle Proteins / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; C096485:Smyd1 protein, mouse; D014157:Transcription Factors; D015544:Inositol 1,4,5-Trisphosphate